Diagnosis and treatment status of inoperable locally advanced breast cancer and the application value of inorganic nanomaterials

Locally advanced breast cancer (LABC) is a heterogeneous group of breast cancer that accounts for 10–30% of breast cancer cases. Despite the ongoing development of current treatment methods, LABC remains a severe and complex public health concern around the world, thus prompting the urgent requirement for innovative diagnosis and treatment strategies. The primary treatment challenges are inoperable clinical status and ineffective local control methods. With the rapid advancement of nanotechnology, inorganic nanoparticles (INPs) exhibit a potential application prospect in diagnosing and treating breast cancer. Due to the unique inherent characteristics of INPs, different functions can be performed via appropriate modifications and constructions, thus making them suitable for different imaging technology strategies and treatment schemes. INPs can improve the efficacy of conventional local radiotherapy treatment. In the face of inoperable LABC, INPs have proposed new local therapeutic methods and fostered the evolution of novel strategies such as photothermal and photodynamic therapy, magnetothermal therapy, sonodynamic therapy, and multifunctional inorganic nanoplatform. This article reviews the advances of INPs in local accurate imaging and breast cancer treatment and offers insights to overcome the existing clinical difficulties in LABC management. Graphical Abstract


Introduction
Locally advanced breast cancer (LABC) is a significant and complicated global public health concern.Currently, there are approximately 400,000-550,000 fresh cases of LABC diagnosed annually worldwide, accounting for 10-30% of all breast cancer cases [1][2][3][4].In less-developed medical regions and several developing countries, the percentage of new breast cancer cases that are LABC can be as high as 40-60% [5].LABC is defined as having a large tumor (> 5 cm, T3 according to AJCC 8th edition), a tumor of any size with involvement of the skin or chest wall (T4), a tumor with clinically detectable fixed regional axillary nodes (N2), or a tumor with ipsilateral infraclavicular, supraclavicular, or internal mammary lymph nodes (N3), excluding distant metastasis [6].LABC can be divided into two types: operable LABC and inoperable LABC.Overall, LABC has a poor prognosis due to the presence of an enormous tumor burden, advanced stage, and a high probability of distant metastasis.The 5-year survival rate for LABC ranges from 48 to 52%, whereas the 10-year survival rate is less than 41% [7][8][9].In particular, for inoperable LABC, the inability to surgically remove the tumor from the breast and regional lymph nodes allows tumor cells to infiltrate the lymphatic vessels in the skin easily.This event leads to regional and contralateral breast invasion, dramatically increasing the probability of hematogenous metastasis and ultimately leading to a worse prognosis.Systemic treatment is the primary treatment for inoperable LABC [10].Without timely and effective systemic treatment, patients often suffer from complications caused by local tumor invasion, such as ulceration, bleeding, odor, pain, and severe upper limb edema.An even bigger concern is that these patients often experience distant metastasis within a short period, which can inevitably result in death.Neoadjuvant therapy before surgery assists in reducing the stage of inoperable LABC, providing the opportunity to undergo radical surgical treatment.However, patients who do not respond well to current neoadjuvant therapy regimens are unable to undergo radical surgery.Instead, they can only receive palliative systemic treatment and radiotherapy.This inability to effectively control disease progression significantly increases the likelihood of distant metastasis and results in a poor prognosis.
The field of inorganic nanoparticles (INPs) has witnessed significant progress, leading to the emergence of innovative approaches and strategies for diagnosing and treating breast cancer [11].These methods capitalize on the specific biological characteristics of inorganic nanomaterials, which have shown tremendous potential for translational clinical applications, particularly in addressing the treatment restrictions of inoperable LABC.This article first introduces the current diagnostic and treatment pathways and challenges for inoperable LABC.This paper primarily focuses on the new technological applications of nanomaterials in the precise imaging assessment of breast cancer, radiosensitization, novel local treatment approaches, and the applications of diagnostic and therapeutic studies.This study aims to provide a comprehensive review of the diagnosis and treatment of inoperable LABC from the perspective of INPs, as well as offer fresh insights into the translational clinical applications of these INPs.

Current treatment protocol and challenges in the management of inoperable LABC
Presently, the treatment options for inoperable LABC include local treatments such as surgery and radiotherapy and systemic treatments like chemotherapy, targeted therapy, endocrine therapy, and immunotherapy [6].Systemic treatment remains the primary approach, supplemented by local treatment due to the significant burden of tumors, extensive invasion, and the high risk of distant metastasis.The selection of systemic treatment regimens needs to be tailored to the subtype of breast cancer.Most patients with inoperable LABC inevitably must undergo chemotherapy.Endocrine therapy is used in hormone receptor-positive (ER positive and PR positive) breast cancer, whereas HER2-positive breast cancer requires anti-HER2 therapy [12].Optimizing the diagnosis and treatment process for inoperable LABC is essential to enhance treatment outcomes.Compared to the traditional approach of adjuvant systemic treatment plus radiotherapy after surgery, the value of neoadjuvant therapy conducted before surgery is increasingly recognized.It is gradually becoming the widely accepted standard treatment for inoperable LABC [4].Effective neoadjuvant therapy can reduce the stage of inoperable LABC, allowing patients to downstage to radical surgery and receive subsequent intensified adjuvant treatment.This approach has significantly reduced the recurrence and mortality rates of patients with inoperable LABC [7,13].Based on the emergence of additional substantiation from evidence-based medicine, the current treatment protocol for inoperable breast cancer is described as follows (Fig. 1).For patients with inoperable LABC, accurate imaging assessments and pathological diagnosis are crucial in determining the extent of tumor invasion, pathological features, and tumor subtypes.Subsequent treatments involve personalized, subtype-specific neoadjuvant therapies and whole-course imaging monitoring to assess changes in tumor burden and the efficacy of the neoadjuvant therapies according to Response Evaluation Criteria in Solid Tumors (RECIST).The RECIST assessment categorizes tumor response post-treatment as CR, PR, SD, or PD [14].Patients who exhibit a positive response to treatment, with a significant decrease in the tumor size or even complete response (PR/CR), may qualify for BCS or mastectomy.The following treatments include radiotherapy and subtype-specific adjuvant therapies such as endocrine therapy, targeted therapy, and immunotherapy [10,12].Patients who have a relatively effective treatment response but are not suitable for BCS may undergo mastectomy, with or without breast reconstruction.Patients with a poor treatment response, assessed as SD or PD, require local radiotherapy to become eligible for radical surgery and receive subsequent adjuvant therapy.If radiotherapy is unfortunately ineffective, these patients have to enter the palliative systemic treatment stage, which often carries the worst prognosis [15].
The treatment process mentioned above for inoperable LABC emphasizes the importance of achieving the opportunity for radical surgery via effective neoadjuvant therapy as the initial crucial step in treatment, which is necessary for subsequent adjuvant therapy.With the continuous emergence of new treatment drugs such as CDK4/6 inhibitors, immunotherapy, and antibodydrug conjugates, the selection of neoadjuvant therapy regimens has become more diverse and effective.This outcome has further increased the possibility of transforming non-surgical LABC after neoadjuvant therapy into surgical LABC, providing the possibility for radical surgery [10,12].
Another key point for treating inoperable LABC is precise imaging monitoring and assessment.Accurate imaging diagnosis is crucial for making appropriate clinical treatment decisions.A precise imaging assessment of treatment response is essential for accurately determining the viability of radical surgery.Imaging information is a critical reference in clearly identifying surgical resection margins, selecting appropriate surgical procedures, and delineating the target area for local radiotherapy [16].Conventional breast US and MG are not precise enough to confirm the extent of tumor invasion in inoperable LABC, which often exhibits a widespread distribution.Breast-enhanced MRI provides higher imaging accuracy for assessing tumor invasion and is more suitable for evaluating treatment responses [17,18].PET-CT can provide more sensitive monitoring data, especially for detecting distant metastases [19,20].However, for inoperable LABC with extensive regional invasion, the current imaging methods mentioned above are still unable to meet the demands for the complete determination of tumor boundary information due to their limited resolution.
The third key point in treating inoperable LABC is practical local therapy.For cases where neoadjuvant therapy is ineffective and surgery is not feasible, radiotherapy is currently the only viable local treatment option.However, the limited tolerance of body tissues to radiotherapy dramatically hinders the ability to increase radiation dosage.High-dose radiotherapy can result in various complications, such as skin fibrosis, skin breakdown, lung fibrosis, myocardial damage, rib necrosis, brachial plexus injury, and severe edema in the affected upper limb [21].There is an urgent need for the development and clinical applications of novel treatment methods, in addition to radiotherapy, for local treatment to effectively improve the chances of converting patients with non-surgical LABC into candidates for surgery, enabling them to undergo radical surgical procedures.This move will also provide better local control treatment for patients relying on palliative systemic therapy, ultimately improving their quality of life [22].

New solutions for inoperable LABC using INPs
Based on the background above, the diagnostic and treatment challenges related to inoperable LABC must be tackled as soon as possible.This option includes developing and applying novel therapeutic drugs, facilitating advancements in imaging techniques, and exploring and implementing innovative local treatment methods.Systemic treatment drugs for breast cancer have improved significantly in recent years, and numerous reviews have summarized these advancements.This article does not delve into that realm.Instead, it summarizes and analyzes the literature on breast cancer imaging and local treatment.
First, bibliometric analysis was employed to measure the impact of research articles, assist researchers in identifying future research trends, and focus on critical areas of study.This study's authors have conducted a comprehensive bibliometric analysis of the literature related to the applications of nanomaterials in breast cancer over recent decades.This analysis evaluates the research trends and hot topics in diagnosing and treating breast cancer using nanomaterials from a bibliometric perspective.
This study incorporated 755 records that met the search criteria.Figure 2A  Next, the authors analyzed the academic cooperation and exchanges between countries and institutions in this field from 2006 to 2023 and discovered the participation of researchers from 29 countries and regions.Figure 2B provides a global overview of these studies.This study conducted a cluster analysis of the quantity of international collaborative publications and classified these international relationships into six distinct clusters.The thickness of the lines indicates the frequency of collaboration between institutions.Notably, from 2006 to 2023, China and the United States exhibited the closest cooperation, jointly publishing 21 articles.
The researchers next utilized an overlay of network and density visualizations to analyze the keywords and their co-occurrence of nanomaterials in breast cancer research.The top 15 clusters of key hotspots were identified by analyzing 2098 keywords.The three clusters with the most contributions included "different electrochemical biosensors, " "cancer diagnosis, " and "accurate monitoring" (Fig. 2C).A timeline-based analysis was conducted to understand how these clusters were distributed across various periods (Fig. 2D).An evolution of researching themes over time was observed.Early references emphasized nanoarchitectonics and theranostics nanotools, whereas recent publications focused on gene delivery and breast cancer detection employed with nanomaterials.
Keyword co-occurrence analysis revealed that the research hotspots could be divided into eight categories (Fig. 2E).The blue cluster primarily encompassed keywords related to breast cancer, whereas the green cluster was primarily associated with gold nanoparticles (AuNPs).The keywords co-occurring with breast cancer are closely linked to INPs such as iron oxide, gold, silver, and graphene.These keywords also strongly connect to diagnostic techniques like circulating tumor cells (CTC), biosensors, fluorescence, and contrast agents.The bibliometric analysis results clearly demonstrate that the value of INPs applied in breast cancer research is gradually being recognized and emphasized by researchers worldwide.The development and applications of INPs, as one of the hotspots in cancer therapy, offer innovative ideas and solutions for advancing imaging techniques [23].The development and applications of novel inorganic nanomaterial contrast agents have significantly enhanced the anatomical resolution of CT, MRI, and PET-CT [24,25].Furthermore, the development of novel imaging techniques, such as PAI, FI, and SERS, based on inorganic nanomaterial technology, has significantly improved the accuracy of tumor imaging assessment [26][27][28].
In the field of local therapy, INPs have introduced innovative treatment possibilities in the areas of radiotherapy sensitization, PTT, PDT, MHT, and SDT [29,30].These advancements show promising potential for clinical applications.The potential to perform imaging, diagnosis, and treatment simultaneously, known as theranostics, using INPs is exciting.It presents significant opportunities for theranostics applications in the local treatment of inoperable LABC [31,32].The following text will provide a detailed introduction to the progress of translational research on inorganic nanomaterials for their potential clinical applications in diagnosing and treating inoperable LABC.

INPs for the diagnosis of LABC
The bibliometric analysis shows that INPs have made breakthroughs in diagnosing breast cancer by enhancing the signal intensity of various optical imaging to increase sensitivity and specificity, especially the development of multimodal imaging technology that facilitates earlystage diagnosis to guide personalized and precision treatment.
Breast cancer is a complex disease characterized by the development of malignant tumors in breast tissues, often manifesting as lumps and changes in the breast shape or texture.Its progression varies widely based on molecular tumor subtypes, such as hormone receptor status, the timing of therapeutic intervention, and individual patient factors.
Based on the 2015 St. Gallen early breast cancer international expert consensus [48], breast cancer can be categorized into four main types by the expression of specific biomarkers: (1) Luminal A: this type is hormone receptor-positive (ER positive and PR positive) and HER-2 negative.It is one of the most common forms of breast cancer, accounting for about 60% of all cases.(2) Luminal B: this type is hormone receptor-positive and can be either HER-2 positive or negative, representing approximately 20-30% of breast cancer cases.(3) HER-2 positive: this type is characterized by being hormone receptornegative and accounts for about 10-20% of breast cancer cases.It generally has a relatively poor prognosis.(4) Triple-negative breast cancer (TNBC): this type lacks both hormone receptors and the HER-2 receptor, comprising roughly 10% of breast cancer cases.TNBC typically has a poorer prognosis, is unresponsive to endocrine therapy and targeted treatments, and offers fewer therapeutic options.
Data from the National Breast Cancer Foundation (https:// www.natio nalbr eastc ancer.org/ breast-cancerfacts/) indicate that when breast cancer is detected early at the localized stage, the 5-year relative survival rate can be as high as 99%.This finding underscores the significant benefit of early detection in improving survival outcomes for patients with breast cancer.
MG, an X-ray test of the breast, is a primary method for breast cancer screening and diagnosis [49].However, X-ray image interpretation relies on the experience and subjective judgment of radiologists, leading to potential misdiagnoses or missed diagnoses.Furthermore, mammograms may lack sufficient sensitivity for the early detection of breast cancer, especially in dense breast tissues.
Given these limitations, multiple imageological examinations, including MRI, CT, PET, PAI, SERS, and FLI, can be applied for the early detection of breast cancer.INPs are superior sensitive probe materials due to their unique acoustic, electrical, optical, magnetic, and thermal properties.In recent years, numerous INPs have been used to provide higher-resolution images to detect early breast cancer lesions (Table 1).
The following section will focus on the application and development of INPs in assisting these breast cancer diagnosis techniques.

Magnetic resonance imaging
MRI utilizes powerful magnetic fields and radio waves to generate detailed images of internal structures and organs within the body, thus enabling the identification of malignant breast lesions by analyzing their morphological and dynamic characteristics.Nevertheless, the applications of MRI in breast cancer diagnosis are hindered by certain limitations, such as inadequate spatial resolution and possible toxic side effects associated with conventional contrast agents like gallium [67,68].The application of INPs is a promising solution to overcome these drawbacks.In recent 5 years, it has been widely reported that INPs [69] with iron (Fe), gadolinium (Gd), cobalt (Co), nickel (Ni) manganese (Mn), dysprosium (Dy), holmium (Ho), ferrites (various compositions) and magnetite (Fe 3 O 4 ) have been used as magnetic sensitizers for breast cancer, especially LABC diagnosis, which can enhance MRI signal intensity and resolution.These INPs enhance the contrast between tumors and surrounding normal tissues, easing the detection and localization of tumors.
SPIONs have been extensively investigated as MRI contrast agents due to their low toxicity and preferable biocompatibility.Their target-specific properties enable them to selectively bind to breast cancer cells; moreover, heightened sensitivity enables them to detect subtle changes in breast lesions early.Figure 3 summarizes SPIONs currently available for MRI in breast cancer.Zhou et al. [53] constructed a transferrin-modified gadolinium-iron chelate nanoprobe based on ultra small paramagnetic iron oxide nanoparticles (USPION) named TUG.The obtained TUG demonstrated high biocompatibility even at a high dose of 15 mg kg −1 .More importantly, compared with clinically used Gd-based small molecule contrast agents, TUG can be more engulfed by 4T1 cells, showing much enhanced T 1 -weighted positive MRI in both subcutaneous and orthotopic tumor
In addition to iron nanomaterials, Mona Alibolandi et al. [52] synthesized Gd-doped copper indium zinc sulfide QDs attached with AS1411 DNA Apt (a single strand DNA Apt with high affinity against nucleolin, which is overexpressed at the cell surface as breast cancer marker) for diagnosing breast cancer.They injected the nanomaterial into 4T1 tumor-bearing Balb/c mice and acquired T 2 -weighted MR images 12 and 24 h after injection.Compared with the untargeted agent, the targeted agent linked to AS1411-Apt significantly accumulated at the tumor site, as demonstrated by MRI, highlighting the platform's capability for enhanced tumor targeting and imaging.
Using INPs as magnetic sensitizers in MRI provides advanced capabilities for breast cancer detection and precise targeting.This approach significantly enhances diagnostic efficiency, enabling the early-stage identification and monitoring of disease progression.

Computed tomography and positron emission tomography
Molecular imaging modalities, including PET and CT, have been evaluated for primary breast cancer diagnosis and staging in recent years.These two imaging techniques use nuclides to distinguish normal tissue from diseased tissues, especially for diagnosing tumors [73,74].
Currently, nuclides used in PET and CT contrast enhancement include Gallium-68, FDG, Carbon-11, Nitrogen-13, and Oxygen-15.These isotopes have short half-lives, which imposes strict limitations on their production, transportation, and usage windows.INPs overcome these drawbacks by avoiding radiation exposure issues as novel imaging agents.Flexible size and composition, high biocompatibility, and reduced toxicity and immune responses make them suitable for multimodal imaging.
Shen et al. synthesized mPEG@HGNPs, and the attenuation properties were examined by CT imaging in MCF7 breast cancer cells [56].Compared to HGNPs and iohexol, mPEG@HGNPs demonstrated enhanced CT attenuation intensity and brightness.In xenografted tumor-bearing BALB/c mice, mPEG@HGNPs maintained contrast enhancement at the tumor site for 12 h post-injection (ΔHu 89), outperforming HGNPs (ΔHu 73 at 4 h, ΔHu 10 at 12 h), suggesting prolonged blood half-life and targeted organ accumulation due to reduced uptake by the mononuclear phagocyte system.
Recently, researchers have focused on inorganic QDs to improve their performance in biomedical imaging, cell labeling, in vivo imaging, and other multimodal imaging techniques instead of traditional CT or PET imaging.Hong et al. observed that Ag 2 Te QDs exhibited a remarkably enhanced contrast effect of CT imaging in a concentration-dependent manner in vitro experiment [39].At the equivalent concentration, Ag 2 Te QDs possessed a Hounsfield units value of 99 HU L g -1 .At the same time, iohexol, a commonly used clinical contrast agent, exhibited a value of only 39 HU L g -1 , demonstrating the potential high performance of Ag 2 Te QDs for contrast-enhanced CT imaging.Furthermore, the CT imaging signal of the breast tumor tissue was more than twice as strong at 3 h after injection compared with the pre-contrast image (Fig. 4B).These results indicated that enhanced CT imaging quality provided by Ag 2 Te QDs could result in earlier and more accurate diagnoses.
CT imaging accurately provides anatomical and pathological information.Combined with PET imaging, which offers functional and metabolic insights, this dual-modality approach is highly beneficial for a comprehensive assessment of breast cancer.Furthermore, INPs significantly enhance such dual-modality detection of breast Fig. 4 INPs for the diagnosis of breast cancer.A TUG; B Ag 2 TeQDs; C SWNHs/C18PMH/mPEG-PLA-DOX-Pt; D bMSN@T2-RGD-Acrk; E AuNS; F biosensor that combined CA153, CA125 and CEA antibodies with DTNB, 4MBA, and 2NAT labeled Ag nanomaterials.A Is adapted with permission from [53], copyright 2020 Journal of Materials Chemistry B. B Is adapted with permission from [39], copyright 2020 ACS Applied Materials & Interfaces.C Is adapted with permission from [46], copyright 2018 Theranostics.D Is adapted with permission from [86], copyright 2019 Nanomedicine.E Is adapted with permission from [62], copyright 2018 nanoscale.F Is adapted with permission from [92], copyright 2018 Talanta (See figure on next page.)Fig. 4 (See legend on previous page.)cancer, leveraging the strengths of both CT and PET for improved early diagnosis.
Beiki et al. used 68 Ga-DOTA-BN-TMC-MNPs (SPIONs-based) nanomaterials to perform PET and CT dual-modality imaging of nude mice subcutaneously implanted with T-47D cells [65].Enhanced tumor visibility was observed in PET imaging even at a lower nanoparticle concentration of 0.62 mg/mL due to its high sensitivity.Besides, the SUVmax (standardized uptake value) ratio and SUVpeak ratio of the tumor vs control group were calculated using PET/CT scans at 120 min and obtained as 19.6 and 15.4, respectively.These results indicated that the high uptake of this nanoparticle in the tumor lesions could allow for precise tumor imaging for an early diagnosis of breast cancer.
The application of INPs to CT and PET imaging has significantly revolutionized the diagnosis efficiency of breast cancer.By providing enhanced contrast and detailed dual-modality imaging, this innovation enhances diagnostic precision and supports more sensitive monitoring of disease progression.

Photoacoustic imaging
PAI, an emergent non-invasive imaging technique, combines the benefits of ultrasonic imaging with greater flexibility in the selection of photosensitizers (PSs) [75].The images of internal tissues are produced according to the photoacoustic effect.This method involves directing short laser pulses at tissues, which absorb the light and rapidly expand thermally, generating acoustic waves.These waves are detected by ultrasonic sensors, and the data are used to create detailed images that reflect the tissues' optical absorption characteristics, which are crucial for diagnosing cancer [76].The effect of imageological examinations is affected mainly by tissue thickness.Despite the variations in breast tissue thickness among individuals, typically ranging from a few centimeters to tens of centimeters, PAI's penetration depth of 7 cm is adequate to cover most breast tissues.Along with its spatial resolution of 100 µm, PAI enables the detection of subtle changes associated with early-stage breast cancer, thus significantly enhancing the accuracy of early diagnosis and distinguishing tumor types and progression stages [77,78].PAI primarily generates images based on the light absorption of biological tissues.However, benign and malignant tumors exhibit similarities in specific physiological and biochemical characteristics, such as blood vessel density, oxygenation levels, and metabolic activity [79,80].Consequently, PAI may pose challenges in distinguishing malignant tumors from benign tumors.Moreover, image quality largely depends on the stability of PAI signals.Researchers have turned to INPs for targeted and stable imaging to address these limitations.
Recently, gold, antimony, bismuth, cobalt, copper, palladium, silver, titanium, tungsten, uranium, carbon nanomaterials, and graphene have been utilized as imaging elements in PAI to provide high-contrast photoacoustic signals that significantly enhance the accuracy and efficiency of breast cancer diagnosis [69].
Ran et al. synthesized CuS@mSiO 2 -PFP-PEG (CPPs) nanocomposites and found them highly effective as a contrast agent for PAI [81].Their study observed that the photoacoustic signal intensity linearly increased with CPP concentrations ranging from 100 to 1500 μg/mL.Furthermore, they conducted experiments on tumorbearing mice models, where they acquired PAI of tumor sites at various time intervals (0, 3, 6, 12, 24, and 48 h) following the intravenous injection of CPPs.They discovered that the CPPs increased the PA signal intensity of the tumor regions from 0.073 to 0.161 within 24 h postinjection, demonstrating the accumulation of CPPs in the tumor sites.These results highlight the potential of CPPs in enhancing the PAI of tumors, aiding in more accurate and effective diagnosis.
Zhang et al. used single-walled carbon nanohorns (SWNHs) as contrast agents for PAI and synthesized SWNHs/C18PMH/mPEG-PLA-DOX-Pt [46].They focused on its potent PAI characteristics for effective tumor targeting and accumulation.PAI analysis revealed that after intravenous administration at 10 mg/kg in 4T1 tumor-bearing mice, the nanohorns progressively accumulated in the tumor.Notably, significant accumulation was observed at 24 h post-injection in both tumor vessels and parenchyma.These characters underscore the nanohorns' ability to persist in the tumor environment, enabling clear and detailed imaging crucial for precise tumor diagnosis (Fig. 4C).
Xu et al. conducted Janus-structured chitosan/gold nanohybrids (J-ACP) for PAI-guided PTT in breast cancer [59].They administered 100-μL J-ACP (5.23 mg/mL) intravenously to 4T1 tumor-bearing mice and recorded PA signal intensity at different time points.Their results demonstrated J-ACP actively accumulating at tumor sites and significantly enhanced PAI signals, emphasizing its potential in breast cancer diagnostics.
INPs utilized as imaging elements in PAI significantly boost breast cancer's detection capabilities [82] and improve the dynamic observation and diagnosis precision of tumors by providing high-contrast signals.

Fluorescence imaging
FLI is a technique that utilizes the fluorescent properties of substances to emit light at specific wavelengths.FLI is characterized by real-time detection and high sensitivity, enabling early detection of breast cancer cells and small metastases.However, in breast cancer diagnosis, FLI requires highly selective and stable fluorescent probes, whereas unstable or non-specific binding may result in misdiagnosis or missed diagnosis.INPs can be designed with higher stability and specificity for enhanced imaging accuracy and reliability.Some nanomaterials, such as silicon nanomaterials, carbon nanomaterials (nanotubes, graphene, etc.), metal sulfur QDs [usually bound to zinc (II), cadmium (II), Selenide, sulfide), upconversion nanoparticles (UCNPs) (erbium (III), thulium (III), ytterbium (III), etc.] [33] as fluorescent contrast agents can achieve early detection of breast cancer via active or passive targeting.In addition, by selecting different surface modifiers or functional molecular links, QDs can bind specifically to the biomarkers of breast cancer cells, thus achieving a higher accuracy of early diagnosis [83][84][85].
Dai et al. compared the fluorescence contrast effects of erbium-based rare-earth nanoparticles ErNPs-TRC105 (an antibody to CD105 on tumor vasculatures) with IRDye800-TRC105, which is used in human clinical trials for tumor or sentinel lymph nodes localization [35].The result indicated that at 24 h post-injection, mice injected with ErNPs-TRC105 demonstrated a high tumor NIR-IIb emission signal with a low background signal over the body (5 ms of exposure time), compared to the high background body signal for mice injected with IRDye800-TRC105.
Zhan et al. developed a photo-triggered cycloaddition reaction via bMSN@T2-RGD-Acrk, a non-toxic, biocompatible fluorescent silica nanoprobe, demonstrating a strong affinity for 4T1 breast cancer cells with significant accumulation of cytoplasm [86].Notably, in vivo FLI performed 4 h after the intravenous injection of the nanoprobes revealed that bMSN@T2-RGD-Acrk exhibited higher fluorescence intensity in transplanted orthotopic 4T1 tumors.STBRs (signal-to-background ratios) of bMSN@T2-RGD-Acrk were nearly 2.4-fold greater than bMSN@T2-AM, suggesting that bMSN@T2-RGD-Acrk, as a targeted fluorescent nanoprobe, has significant binding and imaging capabilities for breast cancer cells, thus holding substantial value for the diagnosis and monitoring of breast cancer (Fig. 4D).
Chen et al. synthesized CQD-KD1, a CQDs conjugated with a recombinant st14 inhibitor (KD1) to target MCF-7 breast cancer cells, which are known for overexpressing st14 on the cell surface [66].CQD-KD1 exhibits robust fluorescent imaging features, showing broad emission spectra with peak emissions around 545 nm when excited at 450 nm.Furthermore, CQD-KD1 demonstrates exceptional photostability, maintaining fluorescence intensity even after 10 h of continuous irradiation of household light (12.5 mW/cm 2 ), significantly outperforming traditional small molecule probes like FITC.They determined the cellular imaging of CQD-KD1 at ex488 and ex546.After pre-incubating with 6.5 mg/mL CQD-KD1, MCF-7 cells exhibited strong fluorescence with the above two channels.The fluorescence was closely aligned with cell membranes, indicating the precise localization of the CQD-KD1.These results indicated that INPs could present a valuable tool in the medical imaging of breast cancer.
The integration of INPs in FLI enables the utilization of highly selective and stable fluorescent probes for specific binding to breast cancer cell biomarkers via active or passive targeting.This approach offers real-time detection and high sensitivity in breast cancer diagnosis, thereby enhancing the accuracy of early detection.However, FLI is influenced by factors such as the selectivity and stability of fluorescent probes and limitations in fluorescent signal penetration depth, which may restrict its ability to detect deep tissues or small micrometastasis.Consequently, researchers focus on improving signal penetration and optimizing probe design via nanotechnology to enhance stability and targeting capabilities.Simultaneously, the multimodal integration of FLI with other imaging technologies like MRI or CT and the development of new NIR FI technology can significantly improve imaging depth and resolution, providing a more comprehensive understanding of disease information during early breast cancer diagnosis.

Surface-enhanced Raman scattering
SERS is performed as a transformative technique that, when integrated with INPs, offers remarkable capabilities in the early diagnosis, precise subtyping, and even the treatment monitoring of breast cancer.The unique fingerprint provided by SERS, characterized by very narrow peaks for individual molecules, allows for high accuracy and the simultaneous detection of multiple analytes, thereby significantly advancing the field of breast cancer diagnostics [87,88].
Bardhan et al. demonstrated an accurate SERS-based detection of TNBC biomarkers both in vivo and in vitro by conjugating Raman tags and monoclonal antibodies specific to PD-L1 and EGFR onto the surface of gold nanostars (AuNS) [62].Multiplexed SERS longitudinal study of the functionalized AuNS was performed after administering retro-orbital injections to nude mice bearing MDA-MB-231 TNBC xenografts.They pre-blocked both PD-L1 and EGFR as negative controls.Raman signals of pre-blocked groups decreased by about 30% compared with the unblocked group, indicating that the nanomaterial is sensitive and specific to distinguish breast cancer with different expression levels of PDL1 and EGFR.This labeled-AuNS could also accurately detect the expression status of different biomarker signals in the same tissue slice in vitro.Furthermore, the electron microscopy results demonstrated that the nanomaterial was endocytosed by tumor, liver Kupffer cells, and spleen macrophages, indicating that it could be used for SERS imaging and removed from the body (Fig. 4E).
Jia et al. constructed a SERS chip based on Ag 2 O-Ag-Psi to rapidly detect breast cancer [89].In this platform, the Ag 2 O-Ag nano core shell, with a diameter of 40-60 nm, is embedded in a porous silicon substrate.Compared with the conventional Raman spectrum, the SERS spectrum of breast cancer patient's serum samples greatly improved the intensity of multiple leading spectral bands representing diverse biochemical components.By calculating 10 data points at 1157 cm -1 , 1518 cm -1 , 1153 cm -1 , and 1516 cm -1 , the relative standard deviations of the intensity of Raman shifts were 4.6%, 5.1%, 2.5%, and 3.1%, respectively, which indicate that SERS signals exhibit excellent consistency for accurate breast cancer diagnosis.
The expression of several serum exosome-derived miR-NAs is correlated with different breast cancer subtypes and could serve as potential biomarkers for breast cancer diagnosis.Sim et al. developed a SERS (based on AU) sensing platform for quantitatively determining exosomal miRNAs [90].To evaluate the efficiency and accuracy of the developed SERS sensor, they conduct a recovery test by adding known concentrations of miR-21, miR-212, and miR-200c to human serum.Using this SERS-based sensor, they obtained high analytical recovery rates of these miRNAs as 95.28%, 101.68%, and 98.34%, respectively, with a relative standard deviation of 3.03%, 4.72%, 3.61%, respectively.Data measured by this sensor are highly consistent with the PCR results, suggesting the potential use of INPs-modified SERS sensor in the classification diagnosis of breast cancer.
Maiti et al. utilized AuNPs, which measured 40-45 nm in size, and served as the SERS substrate for the development of Raman-label surface-enhanced Raman scattering (RL-SERS)-nanotags [91].SERS nanotags demonstrated significant sensitivity and specificity in detecting breast cancer biomarkers across different cell lines.SERS nanotags effectively identified respective biomarkers for the MCF-7 cell line (ER and PR positive) and the SK-BR-3 cell line (HER2 positive).In the triple-negative MDA-MB-231 cell line (ER−/PR−/HER2−), they showed negligible expression, confirming their specificity.In the tissue analysis, the sensitivity and specificity for single biomarker detection were 95% and 92%, respectively, 88% and 85% for duplex, and 75% and 67% for triplex analysis.The study also demonstrated the capability of SERS nanotags in the HER2 grading of breast cancer tissue samples, differentiating between 4+/2+/1+ HER2 expression levels with Raman intensity ratios of 3.67 ± 0.51, 2.17 ± 0.2, and 1.75 ± 0.15, respectively, correlating well with fluorescent in situ hybridization (FISH) analysis.
These results indicated that SERS shows excellent potential in the early diagnosis and precise typing of breast cancer.Combining with INPs, SERS not only plays a key role in the diagnosis of breast cancer but also shows significant value in efficacy diagnostics.

Biomarker blood test
Blood biomarkers, such as carbohydrate antigens 15-3 (CA15-3), carcinoembryonic antigen (CEA), CA 27.29, HER2/neu, and CTCs, are primarily used to clinically assist in diagnosis and monitor the response to the treatment or recurrence of breast cancer [93][94][95][96].However, standard laboratory medical testing techniques, including ELISA or other immunochemical methods, often fall short in early screening due to their limited sensitivity and specificity.INPs offer more accurate detection and quantification of breast cancer biomarkers at lower concentrations with enhancing fluorescence [97,98].In addition, the flexible customization of surface properties improves the selective adsorption with specific breast cancer antigens [91], thus facilitating an accurate early diagnosis and provision of precision medicine, significantly impacting treatment outcomes [99].Table 2 summarizes the applications of nanomaterials for breast cancer blood tests and corresponding targets in past years.
Cui et al. introduced a microfluidic biosensor that combined CA153, CA125, and CEA antibodies with DTNB, 4-mercaptobenzoic acid (4MBA), and 2-naphthalenthiol (2NAT)-labeled Ag nanomaterials to detect corresponding antigens for breast cancer diagnosis [92].This microfluidic biosensor could perform a reliable quantitative analysis of blood biomarkers in actual samples, and the detection results were consistent with those of commercial ELISA kits.The limits of detection (LOD) for CA153, CA125, and CEA in serum with the ELISA technique were found to be 0.028 U/mL, 7 U/mL, and 0.02 ng/mL in PBS, respectively [100][101][102].Although microfluidic biosensor based on INP achieved a test sensitivity of 0.01 U/mL, 0.01 U/mL, and 1 pg/mL, it strongly highlights the application value of this microfluidic chip in an early diagnosis of breast cancer (Fig. 4F).
Madrakian et al. developed a biosensor utilizing singlewall carbon nanotubes (SWCNTs) covalently linked to the monoclonal antibodies for tissue plasminogen activator (tPA) [103].This biosensor demonstrated a linear response range from 0.1 to 1.0 ng/mL with a remarkably low detection limit of 0.026 ng/mL, crucial for early breast cancer detection.Compared to traditional methods like HPLC and ELISA, this biosensor accurately detected low-concentration biomarkers in serum and is suitable for early auxiliary breast cancer diagnosis.
Zheng et al. developed a homogenous Magneto-Fluorescent Exosome (hMFEX) nanosensor for the rapid and on-site analysis of tumor-derived exosomes [104].This nanosensor was used to detect exosomes in a dynamic range spanning five orders of magnitude with a LOD of 6.56 × 10 4 particles/µL.The hMFEX nanosensor could analyze tumor-derived exosomes in 80 μL of centrifugal plasma from breast cancer patients, demonstrating excellent clinical diagnostic efficacy (AUC = 0.950, sensitivity = 86.11%,specificity = 90%).This study highlights the value of the nanosensor in diagnosing breast cancer, particularly in point-of-care approach.
Integrating INPs in blood tests for breast cancer diagnostics improves the accuracy and speed of diagnostic processes.It also opens new avenues for non-invasive, real-time monitoring of disease progression and treatment response.This innovative approach holds great promise for the future of cancer diagnostics, potentially transforming patient care and improving survival rates.Currently, the applications of INPs in breast cancer diagnosis show excellent promise for overcoming these limitations compared to conventional diagnostic methods.Using INPs as contrast agents can enhance image clarity and specificity in MRI/CT/PET scans while improving imaging contrast and fluorescence signal stability in PAI/FLI scans.Furthermore, INPs can improve the detection sensitivity and specificity when applied to SERS technology or blood biomarker testing in clinical laboratories.The future development and optimization of nanotechnology are expected to enhance the critical role of these materials in improving breast cancer diagnosis accuracy while reducing costs and invasiveness and enhancing patient comfort.

INPs for the treatment of LABC
Practical guidelines for treating LABC, especially TNBC, are still lacking [125,126].Drug resistance to chemotherapy, the inability to reuse radiotherapy after a specific dose, and tumor recurrence after surgery, leading to difficulty in secondary resection, are some major obstacles.Thus, novel methods must be investigated urgently.

Radiotherapy
Radiotherapy, as an effective treatment for the local control of LABC, also has potential or acute side effects [127].Developing new biosafe radiosensitizers is an effective solution.INPs-based radiosensitizers can enhance the susceptibility of tumor cells to ionizing radiation, resulting in DNA damage and the inhibition of DNA repair while increasing the oxidative stress level to induce autophagy and apoptosis.In addition, the occurrence of other biological effects, such as cell cycle inhibition and endoplasmic reticulum stress, ultimately led to cell death and improved the efficacy of radiotherapy [128][129][130].In recent years, the application of INPs in radiotherapy focuses on high Z materials, primarily gold, silver, platinum, Gd, and so on, which can amplify radiation dose deposition due to their high atomic numbers and strong photoelectric absorption coefficient [129,[131][132][133].At the same time, high Z materials, especially metals, tend to be chemically inert, which could reduce damage to healthy cells.Based on the favorable biocompatibility and excellent radiosensitization potential of these metal nanomaterials, Yook et al. developed Au NPs linked to β-particle emitter 177 Lu and panitumumab to create 177 Lu-T-AuNP as novel neoadjuvant brachytherapy for LABC [134].In long-term monitoring, 177 Lu-T-AuNP-based radiotherapy arrested tumor growth, which stopped after 90 days of treatment with no normal tissue toxicity, whereas mice's survival time was extended to 120 days.Their work proposed a new approach for applications in LABC.In another study, Rajaee et al. reported the radiosensitizing ability of PEG-modified bismuth gadolinium oxide (BiGdO 3 -PEG NPs) in MCF-7 and 4T1 breast cancer cells (Fig. 5A) [135].BiGdO 3 -PEG NPs could enhance the radiosensitivity of MCF-7 and 4T1 cell lines, with a radiation sensitizer enhancement ratio (SER) of 1.75 and 1.6, respectively.BiGdO 3 -PEG NPs can effectively inhibit the growth of tumor cells under low-dose irradiation.Moreover, more high Z metals, including nanoparticles with gold silicon shells as the core (AuN@SiO 2 and AuS@SiO 2 ) [136], nanoparticles coated with ultrasmall gold nanocrystals (Au@Cu-Sb-S) [137], cerium oxide nanoparticles coated with the anticancer drug neotenic acid (NGA-CNPs) [138], highly biocompatible poly (vinylpyrrolidone)-coated Ta nanoparticles (Ta@PVP NPs), have been identified as candidates for improved LABC radiation therapy [139].
As a recognized radiosensitizer, iodine has been used in clinics since the last century [140][141][142].However, its short half-life and low rate of tumor retention have limited its application [143].Cline et al. designed the poly maleic anhydride-alt-1-octadecene (PMAO)-coated KI nanoparticles (PMAO-KI NPs).For the first time, they evaluated the potential of KI NPs as a radiosensitizer to enhance radiotherapy in MCF-7 breast cancer cells (Fig. 5B) [144].Their work employed the Na + /I − symporter (NIS) for the iodine uptake delivery and radiosensitization, whereas NIS is expressed in most breast cancer cells.The polymer coating extends the half-lives of the KI NPs.The results demonstrated that PMAO encapsulation doubled the intracellular iodine content compared to the control group.Moreover, after using trans-retinoic acid (tRA) to promote the expression of NIS, the intracellular iodine level was further enhanced to achieve about 1.25 pg/cell, which can exert a radiosensitizing effect.In the presence of tRA, the cell survival rate of PMAO-KI NPs after 5 Gy irradiation was further reduced by 34.22% compared to that without tRA.Next, radiation therapy was performed following the injection of PMAO-KI NPs intrathecally in an MCF-7 tumor-bearing mice model.The results exhibited significant tumor regression.Patients with LABC often receive multiple radiotherapy before surgery.The half-life of PMAO-KI NPs and intracellular iodine content can be increased to achieve sustained iodide release and radiosensitization by modifying the appropriate coating thickness; thus, one injection that can benefit multiple radiotherapy sessions will be possible.
Radiotherapy is still a common clinical strategy for the management of LABC.Developing INPs with high biocompatibility and excellent sensitization effects is urgently needed to ameliorate the existing radiotherapy situation.

Phototherapy
Phototherapy is selective, adjustable, and non-invasive.Its application scope is limited because the penetration capacity and depth of the laser usually are less than 5 cm [145].However, as an accessory organ of the human body, the lesion mammary gland is relatively shallow compared with other organs, making phototherapy undoubtedly suitable for treating LABC [146,147].Meanwhile, compared with radiotherapy, phototherapy uses a low-energy laser and minimizes skin toxicity, which is a good option for those who can no longer receive radiation [148].At present, phototherapy primarily focuses on PTT and PDT.PTT uses the power of photothermal agents (PTAs) to absorb light and convert energy into heat [149].The temperature range of photo-induced hyperthermia is about 40-48 °C, which can achieve the purpose of tumor ablation while minimizing damage to adjacent healthy cells [147,150].However, PDT uses PSs to interact with active biomolecules under light excitation to produce reactive oxygen species (ROS) to kill tumor cells by inducing apoptosis, necrosis, and autophagy [151].
Besides, researchers demonstrated that INPs have favorable physical and chemical properties, stability, biocompatibility, upconversion characteristics, etc., which are competent in the role of PSs and PTAs with perfect application potential [152,153].When we choose the light source, NIR light is undoubtedly a suitable and potential one.Biological transparency windows NIR-I (750-1000 nm) and NIR-II window (1000-1700 nm) have high tissue penetration and retention with low side effects [154,155].The combination of INPs and NIR light has shown promising results in treating LABC.This includes but is not limited to the following materials.

Photothermal therapy
PTT relies on efficient photothermal conversion agents.Among the many photothermal conversion agents, noble metal materials, including Au, Ag, Pt, and Pd, are the most extensively investigated due to their antioxidant properties [156].Gold nanomaterials have been studied the most due to the advances in synthesis, suitable absorption, and strong stability under biologically relevant conditions [157,158].Meanwhile, gold-based nanomaterials had already been employed in the research on PTT for breast cancer as early as 2003 [159].Hirsch et al. first designed the gold-silica nanoshells for the PTT in SK-BR-3 cells.After the irradiation by NIR (820 nm, 4 W/cm 2 ) for 4-6 min, the temperature of the tumor tissue increased by 37.4 ± 6.6 °C, which could cause irreversible damage to tumor cells.LABC is classified as TNBC in approximately one-third of cases [160].To develop a novel photothermal conversion agent for the treatment of TNBC, Cheng et al. designed a novel microwave-triggered heat shock protein (HSP)-targeted gold nanosystem (cmHSP-AuNC) to improve the accumulation of gold nanomaterials by specifically targeting 4T1 cells (Fig. 6A) [161].Microwave irradiation triggered the overexpression of HSP in 4T1 cells, at which time anti-HSP monoclonal antibodies in the nanosystem can improve the accumulation of nanomaterials in 4T1 cells [162,163].After treatment by 808-nm NIR (1.0 W/ cm 2 ), the tumor inhibition rate of microwave-triggered cmHSP-AuNC was 98.48%, which was significantly higher than that in the non-microwave stimulated group (44.20%).As PTT research advances, the current trend is to develop INPs with lower laser energy consumption while maintaining higher photothermal conversion efficiency.Li et al. prepared core-hell nanostars (AuNS@CP NPs) with a AuNS core and a metallic drug coordination polymer (CP) shell [164].AuNS@CP NPs have a temperature increase of about 35 °C under 808nm irradiation (0.5 W/cm 2 , 3 min), which could produce significant photothermal ablation ability, killing 96% of 4T1 cells.
In addition, many other materials, such as sulfide, graphene, and transition metals, including QDs, metal oxide NPs, exhibited high photothermal conversion efficiency and have the potential in LABC treatment [165][166][167][168].For instance, MnFe 2 O 4 [169], AS-BSA-MnO 2 [170], ultrafine graphene oxide (UGO) [171], PDA-DTC/Cu-MnO 2 [172], CuS, Cu 2 − x S, and Cu 2 − x Se [173][174][175][176] are up-and-coming candidates for the treatment of breast cancer.Surface modification strategy is an important approach to improve the biocompatibility of NPs [177].For example, Ying et al. developed a novel biocompatible nanoparticle CuS@BSA-NB2 for HER2-positive breast cancer treatment (Fig. 6B) [178].CuS is modified by BSA to decrease cytotoxicity and conjugated with the HER2 nanobody (NB2) to create the CuS@BSA-NB2 nano-complex.In this work, CuS@ BSA-NB2 has shown the ability to specifically target MDA-MB-231/HER2 cells.As an excellent PTA, CuS@ BSA-NB2 could rapidly reach 59 °C under 808-nm (1 W/cm 2 , 4 min), effectively killing more than 60% of MDA-MB-231/HER2 cells.Summarily, their work presented fresh insights on the treatment of HER2-positive breast cancer.PTT showed application potential in the treatment of LABC.Representative examples of INPs applied to the PTT for breast cancer treatment in the past decade are briefly summarized in Table 3, providing insights into INPs preparation strategies to overcome different breast cancer subtypes.

Photodynamic therapy
Because of its minimally invasive and selective characteristics, the applications of PDT in breast research have made significant progress.Traditional PSs like hematoporphyrin derivative and photofrin have more or less defects, such as low chemical purity, cutaneous phototoxicity, and long half-life [195,196].The accumulation of hydrophobic PSs represented by zinc phthalocyanine in an aqueous solution also affected the therapeutic objectives [197].The construction of PS based on a nano platform can improve these problems.Due to their high stability, adjustable size, optical properties, and accessible surface functionalization, inorganic nanomaterials can be used as carriers to deliver PSs to achieve therapeutic effects [198].For example, hypericin, an example of such PSs limited by its hydrophobicity, can enhance the hypericin uptake by MC-7 breast cancer cells via coupling with gold nanoparticles, thus improving the curative effect of PDT [199].Moreover, the selectivity of breast cancer sites can be further enhanced by surface functionalization modification, like adding target groups or ligands.Zhang et al. designed a hollow mesoporous silica nanoparticle (HMSNs) coated with folic acid-modified BSA (BSA-FA) to form MD@HBF against folate receptor-expressing 4T1 cells [200].HMSNs are used to deliver the PS and methylene blue to perform the PDT effect, and the BSA-FA structure increases the targeting ability of HMSNs (Fig. 6C) [201,202].This design helps to improve the tumor target ability and overcome the defects of traditional PSs.
Not only that, further research revealed that INPs themselves can also play a more critical role than PSs.At the same time, the photothermal conversion ability of inorganic nanomaterials can further enhance the therapeutic effect.It was first reported by Raviraj et al. that precious metal NPs can be sensitized directly to produce 1 O 2 without the use of organic PSs [203].IrO 2 NPs have the function of catalase, which can decompose endogenous H 2 O 2 in the tumor microenvironment to generate 1 O 2 to relieve hypoxia, thus amplifying the therapeutic effect of PDT [204].Yuan et al. combined hyaluronic acid (HA) and glucose oxidase (GO X ) with iridium oxide nanoparticles to create an in situ amplifier: IrO 2 -GOx@ HA NPs (Fig. 6D) [205].In their study, elevated tumor glucose levels were enzymatically converted to H 2 O 2 by GOx.Subsequently, IrO 2 NPs facilitated the conversion of H 2 O 2 into 1 O 2 .The incorporation of HA enhanced the targeting selectivity toward 4T1 breast cancer cells, thereby augmenting the accumulation of ROS and ultimately boosting the PDT effect.Following the treatment with 808-nm NIR light, IrO 2 -GOx@HA NPs significantly killed more than 90% of 4T1 cells and inhibited tumor growth in vivo, showing a pronounced PDT effect.L represents for length; none represents for that not specifically mentioned by the author in the paper; THE 'laser settings' on the right correspond to the 'ΔT' data on the left, representing the concentration of the selected INPs, laser power, and duration time in the photothermal performance test MPH: mercaptopropionylhydrazide; ALA: 5-aminolevulinic acid; DOX: doxorubicin; BBN: bombesin; 177 Lu-DenAuNP-folate-bombesin: 177 Lu-DOTA-dendrimer-AuNPfolate-bombesin; FeOxH-rGO: iron hydroxide/oxide immobilised on reduced graphene oxide nanocomposites; PLL: poly-l-lysine; DIR: 1,1′-dioctadecyl-3,3,3′,3′tetramethylindotricarbocyanine iodide; SPIO: superparamagnetic iron oxide; PLGA: poly lactic-co-glycolic acid; PFP: perfluoropentane; PVCL: poly-N-vinylcaprolactam; Pd Ncap-Her: palladium nanocapsule functionalized with Herceptin; AuNUs: L-dopa functionalized nanourchin-like AuNPs; TAgNPs: triangular silver nanoparticles; LCP-CD/ICG-BsAb NPs: the indocyanine green (ICG) and/or cell death (CD) siRNA-loaded lipid-coated calcium phosphate nanoparticles, functionalized with bispecific antibody (BsAb); HCIONPs: highly crystallized iron oxide nanoparticles; MnPB-MnO x NPs: Mn-enriched photonic nanomedicine; IRFes: magnetically targeted nanoparticles Meanwhile, IrO 2 NPs with high photothermal conversion efficiency can further synergistically improve the curative effect [206].Moreover, black phosphorus (B.P.), as a novel twodimensional metal-free semiconductor, exhibits high biocompatibility, biodegradability, and excellent photocatalytic performance [207,208].Wang et al. designed black phosphorus nanosheets (B.P. nanosheets) for the PDT in breast cancer.They provided the initial empirical confirmation of its efficacy as a PS for generating 1 O 2 , with a high quantum yield of about 0.91, which is higher than standard PS, rose bengal, suggesting its potential to be used in PDT [209,210].The apoptosis rate of MDA-MB-231 cells was 71.5% after light irradiation (660 nm, 1 W/cm 2 , 10 min).Finally, B.P. nanosheets effectively inhibited the growth of tumors in the MDA-MB-231 breast tumor-bearing mice model.Their results provide a new idea for investigating PSs of INPs.
In the early years, several sets of clinical trials evaluated the local control efficacy of PDT in breast cancer treatment [211,212].With the continued development of nanotechnology, it is not difficult to see a bright future for INPs-based PDT to overcome the challenges of LABC.

Magnetic hyperthermia therapy
Hyperthermia combined with neoadjuvant therapy can enhance the therapeutic effect of patients with LABC [213].NPs-based MHT offers a new method to overcome LABC: not just as an adjunctive treatment option, but as an independent therapy.Compared with laser, alternating magnetic field (AMF) has infinite tissue penetration ability, effectively stimulating NPs to achieve hyperthermia [214].Among a wide range of different nanomaterials, iron oxide NPs are the most clinically oriented NPs and have been widely explored for MHT in breast cancer cells [215][216][217].Sun et al. prepared AMF-responsive composite scaffolds (FA-Gel/FeNP) by using folic acidmodified gelatin and hybridized them with citrate-stable Fe 3 O 4 NPs (Fe 3 O 4 -Citrate NPs) (Fig. 7A) [218].This FA-functionalized composite scaffold has a large spherical hole and good interoperability, which can precisely capture MDA-MB-231-Luc breast cancer cells expressing FA receptors.Under the action of AMF (130 Gauss, 373.6 kHz), > 95% of tumor cells were killed.Moreover, FA-Gel/FeNP shows the supporting effect for stem cell differentiation to adipocytes, which has crucial implications for post-treatment or postoperative breast reconstruction.
In multi-group preclinical trials, the combination of hyperthermia and neoadjuvant chemotherapy has been essential in treating LABC [213,219,220].Based on the good magnetic response of magnetic nanomaterials, controlled release of drugs can be achieved to play a synergistic therapeutic effect.Xue et al. developed AMF-responsive DOX-loaded magnetic microspheres (DM-ACMSs) for multimodality breast cancer treatment [221].With the action of AMF, the temperature increased above 50 °C, up to 22.5% of DOX was released, and 95.5% of the MCF-7 breast cancer cells were killed.Furthermore, this innovative DM-ACMSs system showed onoff drug release capability by remotely controlling AMF (Fig. 7B).In addition, all tumors were eliminated in the combination treatment mode with no recurrence under the action of DM-ACMSs toward MCF-7 breast tumors.This AMF-responsive strategy could reduce tissue damage and cooperate with MHT to play an anti-tumor effect, which is a promising application in LABC preoperative treatment.
MHT has been extensively studied in different molecular types of breast cancer cell lines, and the AMF response-based hyperthermia and drug release mechanism are expected to improve the existing neoadjuvant therapy strategies, reduce tissue damage, and improve curative effect.

Sonodynamic therapy
SDT, wherein sonosensitizers employed by US to catalyze the generation of ROS to kill cancer cells, has highly controllable, non-invasive, and deep tissue penetration ability (on the order of centimeters) [222][223][224][225].This promising approach offers a fresh insight into LABC treatment.The execution of SDT hinges on the efficient separation of electron-hole (e − -h + ) pairs within the USactivated sonosensitizers.The resulting e − -h + pairs and the energy released from the activated sonosensitizers further react with surrounding O 2 and H 2 O to generate cytotoxic ROS [226].INPs characterized by stable chemical properties and prolonged circulation time in the blood can effectively reduce phototoxicity, demonstrating remarkable potential as sonosensitizers [227].Loke et al. first reported the applicability of alginate-coated gold nanorods (AuNRs ALG ) as promising sonosensitizers for SDT in breast cancer [228].The results revealed that the AuNRs ALG structure was stable under US irradiation (1.0 W/cm 2 , 5 min).Its ROS production rate constant was 1.96 × 10 -1 min −1 (Fig. 8A), which is three-to eightfold higher than that of the previous studies, such as TiO 2 nanospheres [229], Au-TiO 2 nanosheets [230], or Au-TiO 2 nanocomposites [231].In vitro results demonstrated an 81% killing effect on MDA-MB-231 breast cancer cells.Furthermore, in vivo experiments are expected to verify its potential in LABC treatment.
Developing novel sonosensitizers with narrow bandgaps to effectively separate e − -h + pairs is vital to enhance the generation of ROS in SDT [224,232].In another study, Li et al. designed a novel tin monosulfide NPs (SnS NPs) coated with PEG (SnSNPs@PEG) for the enhancement of SDT in 4T1 breast cancer cells [233].In this work, SnSNPs@PEG with a narrow bandgap (1.18 eV) can produce ROS efficiently under the action of US (1 MHz, 1 W/cm 2 , 50% duty cycle).Simultaneously, SnSNPs@PEG exhibit the photothermal conversion capability, achieving a conversion efficiency of 25.2% under the irradiation of 808-nm NIR (2.0 W/cm 2 ), which can denature tumor collagen, promoting the penetration of SnSNPs@PEG in the tumor, therapy improving the effect of SDT.The tumor was eradicated without recurrence in the 4T1 tumor-bearing mice (Fig. 8B).In conclusion, the SnSNPs@PEG-based therapeutic strategy could improve the accumulation of NPs in tumors and thus improve the therapeutic effect of SDT in breast cancer.
As a new, non-invasive method for treating deep tumors, SDT can increase patient compliance and improve the current treatment status of inoperable LABC through effective local control.optimal preparation strategies for multifunctional nanoplatforms as required.

INPs for the local theranostic application of LABC
One of the most common functions of INPs is that they carry drugs and are easy to modify.Different functions can be performed by screening and loading suitable drug molecules and by functionalization with different ligands.Among the INPs, MSNs with rich porous structure, large surface area, high biocompatibility, and adjustable surface chemistry are widely used as multifunctional design platforms [234].Li and colleagues constructed an HA-coated mesoporous silica-coated Fe 3 O 4 nanoparticles (M-MSN/HA/DI)-based versatile nanoplatforms for the co-delivery of DOX and ICG into MDA-MB-231 breast cancer cells to perform T 2 MR/FL/PA imaging and chemo/PTT capabilities (Fig. 9A) [235].In this work, Fe 3 O 4 NPs play the MRI contrast agent role, whereas ICG, with strong NIR absorption, endows the nanoplatform with PTT and PA/FLI capabilities [236][237][238][239].It is worth noting that M-MSN/HA/DI achieves pH and hyaluronidase-dependent release of DOX, which can reduce the side effects on other organs [240].After the 808-nm irradiation, the cell activity decreased to 14.1%, depicting an apparent synergistic effect, and the tumor growth was inhibited outstandingly upon combination therapy.For different patients with LABC, INPs represented by MSNs can be modified according to specific needs to play a functional therapeutic effect, which is expected to achieve an image-guided individualized treatment mode.
In addition, the imaging or therapeutic function based on the characteristics of INPs itself cannot be ignored.Based on the AMF response ability of Fe 3 O 4 NPs itself, MHT can also be introduced to achieve synergistic therapeutic effects.Ma and colleagues constructed the multifunctional Fe 3 O 4 -Pd Janus NPs (Fe 3 O 4 -Pd JNPs) to synergistically facilitate magnetic and NIR hyperthermia, along with enhanced ROS production for breast cancer treatment (Fig. 9C) [244].Fe 3 O 4 NPs demonstrated excellent responsiveness to AMF and laser and have been extensively studied and utilized in PTT, MHT, and MRI [245,246].Pd nanosheets (Pd NSs) have excellent NIR absorption and photothermal conversion ability, showcasing tremendous application potential for PTT [247].Moreover, leveraging the Fenton reaction mediated by iron nanomaterials and catalytic properties of Pd NSs in an acidic environment, the nanoplatform could react with H 2 O 2 in tumor cells to produce hydroxyl radicals, one type of ROS, to kill tumor cells by inducing apoptosis [247][248][249].In their study, a synergistic amplification strategy of heating and ROS generation was realized under the action of AMF and NIR.In addition, this synergistic strategy achieved complete 4T1 in situ breast tumor suppression, exhibiting outstanding anti-tumor effects.In addition, due to the inherent characteristics of the Fe 3 O 4 -Pd Janus NPs, they also show potential for imaging applications.As a negative T 2 MR contrast agent, Fe 3 O 4 -Pd Janus NPs showed a dose-dependent darkening effect.At the same time, the intensity of the PA signal increased linearly with Pd concentration, indicating the potential for MR/PAI application.This design makes rational use of the physical and chemical properties of INPs and the tumor microenvironment, providing a different perspective for treating LABC.
The continuous advancement in the research and development of INPs has provided a platform for the local diagnosis and treatment of LABC.Their load capacity can be used to optimize traditional drugs' shortcomings or develop novel therapeutic strategies based on their inherent properties, such as laser or AMF-responsive

INPs under clinical trials for breast cancer diagnosis and treatment
Recent years have witnessed an increase in the number of nanoparticles undergoing clinical trials.As of 2024, Clinicaltrials.govlists 90 trials filtered for the condition "breast cancer" and the search term "nanoparticles" [278].There are 12 trials of INPs in breast cancer diagnosis and treatment (Table 5).The majority applications of these trials are focused on lymph node detection, including six trials based on SPIONs (NCT05161507, NCT06104371, NCT05625698, NCT04722692, NCT05985551, and NCT05359783) and three trials based on carbon nanoparticles (NCT04951245, NCT04482803, and NCT03355261).For systemic anticancer therapy, there are two trials based on carbon nanoparticles (NCT06048367) and CdS/ZnS core-shell type QDs (NCT04138342).For local treatment, there is one trial based on AGuIX gadolinium-based nanoparticles (NCT04899908) as a radiosensitizer for improving the efficacy of radiotherapy.Although the progress of inorganic nanomaterials in clinical transformation is not as rapid as fundamental research, the increasing number of clinical trials shows the urgent clinical demand and promising application prospects.

Conclusion and future perspectives
This review extensively discusses the advances in the development of INPs in the local treatment and diagnosis of breast cancer, which has been a hotspot over the past decade.Also, it provides inspiring optimism for

Table 5 INPs under clinical trials for breast cancer diagnosis and treatment
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA).The phase is based on the study's objective, the number of participants, and other characteristics.There are five phases: early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4.Not applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions overcoming the treatment and diagnostic barriers of inoperable LABC.
In the face of inoperable LABC, it is critical to develop minimally invasive control options to reduce the stage of LABC.Compared with deep tumors, multiple physical stimulation techniques such as phototherapy, radiotherapy, and SDT are more applicable for the treatment of superficial types of breast cancer.The introduction of INPs has realized the sensitization effect of tumor cells to these treatment regimens and ultimately enhanced the therapeutic effect.Meanwhile, INPs with long half-life and high biocompatibility ensure the effective and continuous role of the efficacy and overcome the side effects and defects of traditional radiosensitizers, PSs, sonosensitizers, and these intermediums.Meanwhile, MHT based on the AMF response characteristics of magnetic nanomaterials can also achieve image-guided treatment mode in combination with MRI.In future studies, the synergistic application mode of various local treatment schemes must be further explored to develop alternative therapies and regents suitable for LABC.For instance, combining the existing gel technology to prepare biosafe dressing products is suggested.Furthermore, according to different breast cancer types, INPs can be specifically targeted by utilizing presenting biomarkers and screening proper targeting groups.This can effectively improve treatment efficiency while reducing normal tissue damage, thus realizing individualized local treatment more accurately.
In the diagnosis of breast cancer, although MRI, CT/ PET, PAI, FLI, and SERS provide multidimensional diagnostic information, they each have inherent limitations.Despite its ability to offer high-resolution imaging, MRI poses challenges due to its long-lasting imaging time, potential side effects from conventional contrast agents and the risk of false positives.Similarly, CT/PET provides valuable anatomical and functional data but is constrained by spatial resolution and radiation risks.Although PAI and FLI excel in providing high-resolution images, the stability of their fluorescent signals remains a concern.Although SERS technology has shown remarkable success in laboratory studies, further clinical research is required to establish its repeatability.As novel excellent contrast agents, INPs can realize the real-time treatment detection of tumors and achieve multimodal diagnosis and treatment mode, which is expected to improve the accuracy, sensitivity, and specificity of existing diagnostic strategies to the next generation.
Several important issues must be addressed before nanomaterials can be transformed into clinical applications.Although the mammary gland is a superficial accessory organ, it is also necessary to consider the intrinsic toxicity of the INPs.Elements with low intrinsic toxicity should be recommended as far as possible while constructing inorganic nanoplatforms, whereas befitting modification methods should also be employed to cover such metal cores.Various slow-release methods are also proposed to control the amount of nanomaterial systems.In addition, the following influencing factors, such as particle size and shape, surface ligands, and electric charge, are indispensable.These will be most crucial in influencing the pathway to enter cells and the interactions with biological systems.Moreover, the distribution and metabolism of INPs in vivo still require further observation to monitor the long-term toxicity and systematically assess the impact on the organism's function.Moreover, the tumor microenvironment and the characteristics of different tumor molecular phenotypes should also be considered while deciding on reasonable INPsbased nanoplatforms.
In summary, the issues of the clinical status of LABC diagnosis and treatment have prompted urgent demands for a new generation of nanomaterials.At present, the research of INPs primarily focuses on the establishment of various types of breast cancer tumor models.In contrast, the actual exploration of clinical applications on different stages of breast cancer progression (such as early breast cancer, local progression, etc.) is relatively lacking.Nevertheless, it is undeniable that the development of multifunctional INPs provides novel insights into treating inoperable LABC.With technological innovation, the multifunctional nanoplatform based on INPs is also expected to improve the status quo of treatment and diagnosis of inoperable LABC, benefiting patients.
First Hospital of China Medical University, Shenyang 110001, China. 4Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110001, China. 5Department of Breast Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.

Fig. 1
Fig. 1 Treatment of locally inoperable breast cancer and application prospects of INPs.US ultrasound, MG mammography, MRI magnetic resonance imaging, PET-CT positron emission tomography-computed tomography, PAI photoacoustic imaging, FI fluorescence imaging, SERS surface-enhanced Raman scattering, CR complete response, PR partial response, SD stable disease, PD progressive disease, BCS breast-conserving surgery, ALND axillary lymph node dissection, PTT photothermal therapy, PDT photodynamic therapy, MHT magnetic hyperthermia therapy, SDT sonodynamic therapy uses a blue bar to depict the temporal distribution of publications related to the applications of INPs in diagnosing and treating breast cancer.The orange curve illustrates the cumulative total number of publications over the years.From 2006 to 2023, and especially since 2017, the number of annual publications has shown an uptrend, indicating that the application of INPs in breast cancer is emerging as a research hotspot.

Fig. 2
Fig. 2 Bibliometric analysis of INPs applied in breast cancer.A Annual and cumulative trend of publication from 2006 to 2023; B world map of global overview and international collaboration; C 15 clusters of key hotspots divided by CiteSpace software.Distinct clusters are color-coded for identification; D a timeline visualization of 15 clusters generated by CiteSpace software; E keyword co-occurrence analysis map produced by VOSviewer and Pajek.Nanoparticle''s image is adapted with permission from Ref. [33-47], copyright 2019 Journal of Materials Chemistry B, 2020 International Journal of Nanomedicine, 2022 Proceedings of The National Academy of Sciences of the United States of America, 2022 International Journal of Molecular Sciences, 2019 Science Advances, 2017 Nanomedicine, 2020 Acs Applied Materials & Interfaces, 2020 Talanta, 2021 Analytical And Bioanalytical Chemistry, 2018 Science Advances, 2019 Nano Letters, 2018 Acta Biomaterialia, 2020 Journal of Materials Chemistry B; 2018 Theranostics, 2023 Angewandte Chemie-International Edition pronounced performance advantage in MRI imaging [70].Li et al. [71] conducted SPIO/DSPE-PEG5k-(Bom&Cy5) nanomicelles for dual-modality MR/ near-infrared (NIR)/FI imaging in MDA-MB-231 breast cancer cells.The nanomicelles exhibited a high transverse relaxivity (r 2 ) of 493.9 mM −1 s −1 , revealing a linear dependence on Fe concentration and indicating their

Fig. 3 A
Fig. 3 A summary of SPIONs available for MRI in breast cancer diagnosis.A DOX@MMSN-SS-PEI-cit nanoplatforms; B BRBP1-SPIO@mPEG (DiR) nanoparticles; C PMMA/Fe3O4/PAA Jnps; D. CREKA-modified iron oxide (IO) NPs; E DOX-QD-NPs.A Is adapted with permission from [50], copyright 2020 Journal of Colloid and Interface Science.B Is adapted with permission from [72], copyright 2020 Materials Science and Engineering: C. C Is adapted with permission from [51], copyright 2020 Biomaterials Science.D Is adapted with permission from [43], copyright 2019 Nano letters.E Is adapted with permission from [52], copyright 2020 International Journal of Pharmaceutics

Fig. 5
Fig. 5 INPs used in breast cancer radiotherapy.A BiGdO 3 -PEG NPs; B PMAO-KI NPs.A Is adapted with permission from [135], copyright 2019 Physics in Medicine & Biology.B Is adapted with permission from [144], copyright 2021 ACS Nano

Fig. 6
Fig. 6 INPs used in breast cancer phototherapy.A, B The application in photothermal therapy: A cmHSP-AuNC; B CuS@BSA-NB2.C, D The application in photodynamic therapy: C MD@HBF; D IrO 2 -GOx@HA NPs.A Is adapted with permission from [161], copyright 2021 International Journal of Pharmaceutics.B Is adapted with permission from [178], copyright 2022 Frontiers in Pharmacology.Panel C Is adapted with permission from [200], copyright 2023 Colloids and Surfaces B: Biointerfaces.D Is adapted with permission from [205], copyright 2022 Journal of Colloid and Interface Science

Fig. 7
Fig. 7 INPs used in breast cancer MHT.A FA-Gel/FeNP; B DM-ACMSs.A Is adapted with permission from [218], copyright 2023 Advanced Healthcare Materials.B Is adapted with permission from [221], copyright 2018 Journal of Materials Chemistry B

Fig. 9
Fig. 9 INPs for the local theranostic application of LABC.A M-MSN/HA/DI; B Fe 3 O 4 -Au shell -PEG160 NPs; C Fe 3 O 4 -Pd JNPs.A Is adapted with permission from [235], copyright 2020 Expert Opinion on Drug Delivery.B Is adapted with permission from [241], copyright 2021 International Journal of Nanomedicine.C Is adapted with permission from [244], copyright 2019 Nanoscale Horizons

Table 2
Summary of nanomaterials for breast cancer blood test and corresponding targets

Table 3
Representative application of INPs-based PTT in breast cancer with various subtypes With the innovation of modern nanotechnology, more and more inorganic nanomaterials tend to be multifunctional as efficient treatment and diagnosis platforms for LABC.Representative examples of INPs applied to the local diagnosis and treatment of breast cancer in the past years are summarized in Table4, which can provide

Table 4
Summary of breast cancer local theranostic applications based on inorganic nanoplatforms